Over the past two decades, evidence has gradually accumulated in support of the cortical spreading depression (CSD) theory of migraine, which proposes that CSD is the physiological event that underlies the visual aura that precedes the migrainous headache. According to this theory, CSD is also the endogenous process that triggers the migraine headache, presumably through the activation of meningeal nociceptors via the release of excitatory molecules from the parenchyma. Recently, it has been shown that CSD indeed can promote persistent activation of meningeal nociceptors. However, the observed time course of the nociceptor activation following CSD does not easily fit with the mechanisms typically proposed in the CSD theory or the known properties of CSD. First, the onset of this nociceptor activation cannot be accounted for solely by the propagation time of the CSD wave, because in the majority of cases there is a substantial delay between the end of the CSD and the onset of activation. Second, once initiated, the nociceptor activation persists for much longer than can be accounted for by the known actions of the excitatory agents that are released during the CSD wave. Our preliminary data had led us to hypothesize that the persistent and often delayed activation of meningeal nociceptors that occurs in the wake of CSD does not depend upon the brief release of excitatory mediators or a resultant brief nociceptor activation, but rather occurs due to the CSD-evoked vascular and metabolic changes, in particular the cerebral oligemia, hypoxia, and parenchymal lactate elaboration. This working hypothesis will be tested using a series of in vivo electrophysiological recordings of meningeal nociceptors' activity combined with multi-parametric measurements of changes in regional cerebral blood flow (rCBF), parenchymal tissue oxygen tension (tpO2) and lactate concentration as well pharmacological interventions. Specific Aim 1 will determine whether the CSD-related persistent activation of meningeal nociceptors is mediated by the local brief elaboration of excitatory molecules during the CSD phase b) a coinciding brief nociceptor excitation and c) resultant meningeal neurogenic inflammation. Specific Aim 2 will examine the relative contribution of the CSD-evoked cerebral oligemia and hypoxia to the persistent activation of meningeal nociceptors using treatments that inhibit these processes. Specific Aim 3 will employ pharmacological blockers to examine whether CSD-evoked lactate elaboration and ensuing activation of the acid-sensing ion channel 3 (ASIC3) mediates the persistent activation of meningeal nociceptors following CSD. We hope that these studies will provide a better understanding of the endogenous mechanism that play a role in the genesis of migraine headache, which can propel the development of much needed evidence-based approaches to treat this type of pain.